T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

Abstract

Follicular dendritic cells (FDCs) periodically arrange membrane-bound immune complexes (ICs) of T-dependent Ags 200–500Å apart, and in addition to Ag, they provide B cells with costimulatory signals. This prompted the hypothesis that Ag in FDC-ICs can simultaneously cross-link multiple BCRs and induce T cell-independent (TI) B cell activation. TI responses are characterized by rapid IgM production. OVA-IC-bearing FDCs induced OVA-specific IgM in anti-Thy-1-pretreated nude mice and by purified murine and human B cells in vitro within just 48 h. Moreover, nude mice immunized with OVA-ICs exhibited well-developed GL-7+ germinal centers with IC-retaining FDC-reticula and Blimp-1+ plasmablasts within 48 h. In contrast, FDCs with unbound-OVA, which would have free access to BCRs, induced no germinal centers, plasmablasts, or IgM. Engagement of BCRs with rat-anti-mouse IgD (clone 11–26) does not activate B cells even when cross-linked. However, B cells were activated when anti-IgD-ICs, formed with Fc-specific rabbit anti-rat IgG, were loaded on FDCs. B cell activation was indicated by high phosphotyrosine levels in caps and patches, expression of GL-7 and Blimp-1, and B cell proliferation within 48 h after stimulation with IC-bearing FDCs. Moreover, anti-IgD-IC-loaded FDCs induced strong polyclonal IgM responses within 48 h. Blockade of FDC-FcγRIIB inhibited the ability of FDC-ICs to induce T-independent IgM responses. Similarly, neutralizing FDC-C4BP or -BAFF, to minimize these FDC-costimulatory signals, also inhibited this FDC-dependent IgM response. This is the first report of FDC-dependent but TI responses to T cell-dependent Ags.

The inflammatory cytokine IL-18 induces self-reactive innate antibody responses regulated by natural killer T cells

“…4G). These results suggest formation of either underdeveloped GCs or innate-type GCs similar to the T-cell-independent GCs that have been reported to be induced by immune complexes (32). Taken together, our results demonstrate that injections of IL-18 expand the MZB compartment and lead to isotype switch and production of innate-type antibodies in extrafollicular foci and immature GCs.…”

IgM Production by Bone Marrow Plasmablasts Contributes to Long-Term Protection against Intracellular Bacterial Infection

“…Alternatively, persistent Ag or non-specific inflammatory signals may contribute to the maintenance of the CD138 high IgM high population in the BM (67). Persistent Ag may also drive the differentiation of naive B cells into IgM-producing cells that migrate to and establish residence in the BM (68). Another possibility is that the BM functions as a secondary lymphoid organ-like structure (69), thereby facilitating the local generation of Ag-specific IgM-producing cells (39, 70).…”

Stromal cell heterogeneity in lymphoid organs

“…Thereby, FDC efficiently trap immune complexes by their Fc and complement receptors, which have a high stimulatory potential on B cells, and this leads to somatic hypermutation and immunoglobulin (Ig) class switching [39,40] (Figure 3, Table 1). In addition, FDC provide co-stimulatory signals to enhance B cell activation and proliferation [36,41]. This is mediated by the complement components C3 and C4 [42], and by expression of CD137 [43] and CD21L [44] on the FDC surface.…”